The innate immune system plays a role in host defense and homeostasis Innate immune responses are induced when pattern recognition receptors such as Toll-like receptors (TLR) sense the presence of Pathogen Associated Molecular Patterns (PAMPs) or endogenous Damage Associated Molecular Patterns (DAMPs) released by damaged cells. Although acute innate pathway inflammatory responses promote termination of infection and wound healing, chronic activation of this pathway can lead to tissue damage and fibrosis and contribute to various disease states. Thus, there is a need to identify therapeutic strategies that prevent chronic activation of inflammatory pathways.
An estimated 46 million adults in the United States reported to have some form of arthritis, rheumatoid arthritis, gout, lupus, or fibromyalgia. Among them, atherosclerosis, arthritis and the IBD are the most common forms. Atherosclerosis (also known as arteriosclerotic vascular disease or ASVD) is a syndrome affecting arterial blood vessels, a chronic inflammatory response in the walls of arteries, in large part due to the accumulation of macrophage white blood cells and promoted by Low-density lipoproteins (plasma proteins that carry cholesterol and triglycerides) without adequate removal of fats and cholesterol from the macrophages by functional high density lipoproteins (HDL). Atherosclerosis is the usual cause of heart attacks, strokes, and peripheral vascular disease—together called “cardiovascular disease” and is the No. 1 killer in America, with more than 800,000 deaths in 2006. Arthritis is the most common cause of disability in the USA. More than 20 million individuals with arthritis have severe limitations in function on a daily basis. It is estimated that the total cost of arthritis cases is close to $100 billion of which nearly 50% accounts from lost earnings. Each year, arthritis results in nearly 1 million hospitalizations and close to 45 million outpatient visits to health care centers. Inflammatory Bowel Disease refers to two chronic diseases that cause inflammation of the intestines: ulcerative colitis and Crohn's disease. The prevalence rate for IBD is approx 1 in 500 or 0.20% or 544,000 people in the US.
Microtubule-disrupting agents are a new emerging class of anti-inflammatory agents. Microtubules are cytoskeletal structures responsible for maintaining genetic stability during cell division. The dynamics of these polymers can be described by their growth rate at the plus ends, catastrophic shortening, frequency of transition between the two phases, pause between the two phases, their release from the microtubule organizing centers and treadmilling. Microtubule lattice also serves as tracks for the axonal transport of organelles driven by ante-rograde and retrograde molecular motors to generate and maintain axonal integrity. Colchicine and vinblastine are examples of microtubule-disrupting agents that have been used as a class of anti-inflammatory agents. These agents have been shown to reduce TNFα production in macrophages due to their ability to impair tubulin dynamics. In particular, colchicine, a microtubule-depolymerizing agent, has been employed for gout management. However, toxicities limit colchicine's usefulness. Another tubulin inhibitor, vinblastine, used in the treatment of hematological malignancies, has significant toxic side-effects such as leucocytopenias, gastrointestinal toxicity, peripheral neuropathy, and immunosuppression. Interference with microtubule dynamics often leads to programmed cell death, thus, microtubule-binding drugs are currently used to treat various malignancies in the clinic.
The pharmacological profile of microtubule-binding agents has not been ideal. Most of them (i.e. taxanes) need to be infused over long periods of time in the clinic because they are not water-soluble, and can cause hypersensitive reactions due to the vehicle solution. Furthermore, normally dividing cells within the healthy tissues such as intestinal crypts, hair follicles, and the bone marrow are also vulnerable to these agents, leading to toxicities. In addition, nerve cells dependent on molecular traffic over long distances undergo degenerative changes causing peripheral neuropathies. Currently used microtubule drugs, such as vincas and taxanes, are also limited due to the emergence of drug resistance. There have been multiple mechanisms for anti-microtubule drug resistance including over expression of drug-efflux pumps, mis-expression of tubulin isotypes, and perhaps mutational lesions in tubulin itself. It would be desirable to have compounds, compositions and methods for preventing and/or treating various types of innate immune diseases, without significant associated toxicity, that provide increased anti-inflammatory properties to that of microtubule-disrupting agents and other anti-inflammatory agents.